title: HIV-1 entry inhibition by small-molecule CCR5 antagonists: a combined molecular modeling and mutant study using a high-throughput assay.
abstract: Based on the attrition rate of CCR5 small molecule antagonists in the clinic the discovery and development of next generation antagonists with an improved pharmacology and safety profile is necessary. Herein, we describe a combined molecular modeling, CCR5-mediated cell fusion, and receptor site-directed mutagenesis approach to study the molecular interactions of six structurally diverse compounds (aplaviroc, maraviroc, vicriviroc, TAK-779, SCH-C and a benzyloxycarbonyl-aminopiperidin-1-yl-butane derivative) with CCR5, a coreceptor for CCR5-tropic HIV-1 strains. This is the first study using an antifusogenic assay, a model of the interaction of the gp120 envelope protein with CCR5. This assay avoids the use of radioactivity and HIV infection assays, and can be used in a high throughput mode. The assay was validated by comparison with other established CCR5 assays. Given the hydrophobic nature of the binding pocket several binding models are suggested which could prove useful in the rational drug design of new lead compounds.
authors.affiliation: Department of Biology, AnorMED Inc. now Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Labrecque
authors.forename: Markus
authors.initials: M
authors.lastname: Metz
authors.forename: Gloria
authors.initials: G
authors.lastname: Lau
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Darkes
authors.forename: Rebecca S Y
authors.initials: RS
authors.lastname: Wong
authors.forename: David
authors.initials: D
authors.lastname: Bogucki
authors.forename: Bryon
authors.initials: B
authors.lastname: Carpenter
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Tongshuang
authors.initials: T
authors.lastname: Li
authors.forename: Susan
authors.initials: S
authors.lastname: Nan
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bridger
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fricker
authors.forename: Renato T
authors.initials: RT
authors.lastname: Skerlj
mesh_terms: D065100:CCR5 Receptor Antagonists; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D057166:High-Throughput Screening Assays; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000235:genetics; D015203:Reproducibility of Results; D013237:Stereoisomerism; D053586:Virus Internalization
chemical_list: D065100:CCR5 Receptor Antagonists; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5